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Background and Rationale: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. Methods: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within −30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. Results: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). Conclusions: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.

Purpose The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). Patients and methods We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. Results In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. Conclusion Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

INTRODUCTION: We assessed the influence of a best practice alert (BPA) embedded within the electronic medical record on improving hepatitis C virus (HCV) birth-cohort screening by primary care physicians (PCPs). METHODS: Screening by 155 PCPs was monitored during 2 consecutive 9-month periods before and after implementation of the BPA. All tests were reviewed to differentiate true screening from other testing indications. RESULTS: Of 155 PCPs, 131 placed screening orders before and after BPA. Twenty-two PCPs started testing after BPA (P = 0.02). The number of tests placed and screening rates per PCP increased from 16 to 84 and from 3.3% to 13.2%, respectively (P < 0.0001). Before BPA, most PCPs rarely ordered screening HCV tests, whereas a small group of physicians generated most tests, indicative of an underlying power-law distribution. After the BPA, a new group of high-performing PCPs emerged, whose screening patterns were again characterized by a power-law distribution. However, pre-BPA test rates of individual PCPs were not predictive of their post-BPA rates. Overall, the introduction of the BPA narrowed the gap between low- and high-performing testers, indicating that modest increases in testing by a large number of low-performing PCPs could drive substantial improvement in program implementation. DISCUSSION: HCV birth-cohort screening by PCPs was shaped by an underlying power-law distribution. This distribution was preserved after the implementation of a BPA, although pre-BPA test rates were not predictive of post-BPA rates. Increases in test rates by high- and low-performing PCPs both contributed to the overall success of the BPA.

Medical-refractory severe alcoholic hepatitis (AH) has a high mortality. The national frequency, longer term outcomes and regional practices of AH liver transplantation (LT) in the United States are not well described, despite the increasing mortality from alcohol-associated liver disease. We analyzed the trends in frequency and outcomes of UNOS data on 39 455 adult patients who underwent LT from 2014 to 2019, including AH LT recipients. LTs for AH increased 5-fold, from 28 in 2014 to 138 in 2019, varying 8-fold between UNOS regions. Three transplant centers accounted for 50%-90% of AH LTs within each region. The number of transplant centers performing AH LTs increased from 14 in 2014 to 47 in 2019. AH patients were younger (mean = 39.4 years), had higher MELD scores (mean = 36.8), and were more often on dialysis (46.0%) and in ICU (38.4%), compared to other indications (all P

Background: Immune checkpoint inhibition (ICI) is an expanding option in hepatocellular carcinoma (HCC). Antibiotics (ATB) have been shown to reduce response and survival after ICI in other cancers. Methods: Efficacy of ICI is described in patients (pt) from 11 centres (246 USA, 100 Asia, 68 Europe), with median overall (OS), progression-free survival (PFS) and best response (RECIST 1.1) compared between pt with and without ATB exposure in the early immunotherapy period (EIOP) of 30 days before and after ICI initiation. Results: Most of our 414 pt were cirrhotic (297, 71.7%) due to hepatitis C (162, 391.1%) with Barcelona Clinic Stage C (294, 71.0%), Child-Pugh class (CP) A (313, 76.3%) and AFP>400 IU/mL (158, 39.3%). OS was 15.4 mo (95%CI 13.1-17.7) and PFS was 5.3 months (95% CI 4.5-6.0). Most ICI was anti-PD-1 monotherapy (358, 86.5%) and given as 1st (173, 41.8%) or 2nd line (208, 50.2%). Best response to ICI was complete response in 27 pt (6.5%), partial response in 45 (10.9%), stable disease (SD) in 160 (38.6%) and progressive disease (PD) in 161 (38.9%). ATB was given to 167 pt (40.3%), prior to or early after (30 d) ICI initiation (EIOP, 157, 38.0%) or beyond 30 days (21, 5.1%), mostly as beta-lactams (27, 10.9%) or quinolones (26, 10.5%). ATB use was independent of CP class (p=0.76), ECOG performance status (p=0.58) and BCLC stage (p=0.60). mOS in the EIOP+ group was similar to the EIOP- group (13.1 vs 15.5 mo, p=0.92). mPFS in the EIOP+ group was significantly longer than the EIOP- group (7.9 vs 4.2 mo, p=0.004). Observations persisted when stratified by CP class (p=0.42) and ICI type (p=0.92). Partial response rate was higher in the EIOP+ group (17.3% vs 8.6%, p=0.01), although overall objective response and disease control rates were similar between EIOP groups (ORR: 22.7% vs 15.9%, p=0.10; DCR: 64.0% vs 56.6%, p=0.15). Pt in the EIOP+ group were not more likely to experience gastrointestinal AE (EIOP +/- 9.2%/5.4%, p=0.12) or hepatic AE (EIOP +/-, 17.9%/16.5%, p=0.92) of any grade, while severe liver AE (grade 2 or above) were less common in the EIOP+ group (EIOP+/- 2.8%/9.5%, p=0.01). Conclusions: ATB in the 30 d before or after ICI initiation in HCC is associated with prolonged PFS. This is contrary to findings in other solid tumors. Evaluation of the immune-microbiologic determinants of response to ICI in HCC a key research question. Citation Format: Petros Fessas, Muntaha Naeem, Thomas U. Marron, David Szafron, Elad Sharon, Anwar Saeed, Tomi Jun, Sirish Dharmapuri, Abdul R. Naqash, Thoetchai Peeraphatdit, Anuhya Gampa, Yinghong Wang, Uqba Khan, Mahvish Muzaffar, Musharraf Navaid, ChiehJu Lee, Pei-Chang Lee, Anushi Bulumulle, Bo Yu, Sonal Paul, Neil Nimkar, Dominik Bettinger, Hannah Hildebrand, Yehia I. Abugabal, Tiziana Pressiani, Nicola Personeni, Naoshi Nishida, Masatoshi Kudo, Ahmed Kaseb, Yi-Hsiang Huang, Celina Ang, Anjana Pillai, Lorenza Rimassa, David J. Pinato. Early antibiotic exposure delays disease progression following immune checkpoint inhibitor therapy for hepatocellular carcinoma: Evidence from an observational study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 485.

AIM: To determine the prevalence for hepatitis B virus (HBV) and HBV screening and vaccination practices for inflammatory bowel disease (IBD). METHODS: This study is a retrospective, cross-sectional observational study. A retrospective chart review was performed in 500 patients who have been consecutively treated for IBD between September 2008 and January 2013 at the Rush University Medical Center Gastroenterology section. The patients were identified through the electronic medical record with the criteria that they attended the gastroenterology clinic, and that they had a diagnosis of IBD at the time of visit discharge. Once identified, each record was analyzed to determine whether the subject had been infected with HBV in the past, already been vaccinated against HBV, or advised to get vaccinated and followed through with the recommended vaccination. RESULTS: About 254 out of 500 patients (51%) had HBV screening ordered. Among those ordered to have screening tests, 86% followed through with HBV serology. Gastroenterology physicians had significantly different screening ratios from each other (P < 0.001). There were no significant differences in the ratios of HBV screening when IBD specialists were compared to other gastroenterology physicians (0.505 ± 0.023 vs 0.536 ± 0.066, P = 0.66). Of those 220 patients screened, 51% of IBD patients were found not to be immune against HBV. Approximately 50% of gastroenterology physicians recommended HBV vaccinations to their patients in whom serology was negative for antibodies against HBV. IBD specialists recommended vaccinations to a higher percentage of their patients compared to other gastroenterology physicians (0.168 ± 0.019 vs 0.038 ± 0.026, P = 0.015). Present and/or past HBV infection was found in 3.6% of the patients who had serology checked. There was no statistically significant difference in the prevalence of hepatitis B surface antigen (HBsAg) between our study and that reported in previous studies done in Spain (4/220 vs 14/2076 respectively, P = 0.070); and in France (4/220 vs 3/315 respectively, P = 0.159). But, the prevalence of anti-HBcAb in this study was less than that reported in the study in Spain (7/220 vs 155/2076 respectively, P = 0.006); and was not significantly different from that reported in the study in France (7/220 vs 8/315 respectively, P = 0.313). CONCLUSION: The prevalence of HBsAg in our IBD patients was not higher than previously reported European studies. Most IBD patients are not routinely screened or vaccinated against HBV at a tertiary referral center in the United States.